Jursa Thomas, Smith Donald R
Department of Environmental Toxicology, University of California, Santa Cruz, California 95064, USA.
Toxicol Sci. 2009 Jan;107(1):182-93. doi: 10.1093/toxsci/kfn231. Epub 2008 Nov 12.
Manganese (Mn) is a redox-active element, and whereas its uptake, disposition, and toxicity in mammals may depend in part on its oxidation state, the proteins affecting manganese oxidation state and speciation in vivo are not well known. Studies have suggested that the oxidase protein ceruloplasmin (Cp) mediates iron and manganese oxidation and loading onto plasma transferrin (Tf), as well as cellular iron efflux. We hypothesized that ceruloplasmin may also affect the tissue distribution and eventual neurotoxicity of manganese. To test this, aceruloplasminemic versus wild-type mice were treated with a single i.p. (54)Mn tracer dose, or elevated levels of manganese subchronically (0, 7.5, or 15 mg Mn/kg s.c., three doses per week for 4 weeks), and evaluated for transferrin-bound manganese, blood manganese partitioning, tissue manganese disposition, and levels of brain glutathione, thiobarbituric acid reactive substances (TBARS), and protein carbonyls as measures of oxidative stress, and open arena activity. Results show that ceruloplasmin does not play a role in the loading of manganese onto plasma transferrin in vivo, or in the partitioning of manganese between the plasma and cellular fractions of whole blood. Ceruloplasmin did, however, affect the retention of manganese in blood and its distribution to tissues, most notably kidney and to a lesser extent brain and lung. Results also indicate that ceruloplasmin interacted with chronic elevated manganese exposures to produce greater levels of brain oxidative stress. These results provide evidence that metal oxidase proteins play an important role in altering neurotoxicity arising from elevated manganese exposures.
锰（Mn）是一种具有氧化还原活性的元素，尽管其在哺乳动物体内的摄取、分布和毒性可能部分取决于其氧化态，但影响体内锰氧化态和形态的蛋白质尚不清楚。研究表明，氧化酶蛋白铜蓝蛋白（Cp）介导铁和锰的氧化以及负载到血浆转铁蛋白（Tf）上，以及细胞铁外流。我们假设铜蓝蛋白也可能影响锰的组织分布和最终的神经毒性。为了验证这一点，给无铜蓝蛋白血症小鼠和野生型小鼠单次腹腔注射（54）Mn示踪剂量，或亚慢性给予升高水平的锰（0、7.5或15mg Mn/kg皮下注射，每周三次，共4周），并评估转铁蛋白结合的锰、血锰分配、组织锰分布，以及脑谷胱甘肽、硫代巴比妥酸反应性物质（TBARS）和蛋白质羰基水平作为氧化应激的指标，以及旷场活动。结果表明，铜蓝蛋白在体内锰负载到血浆转铁蛋白上或全血血浆和细胞部分之间的锰分配中不起作用。然而，铜蓝蛋白确实影响锰在血液中的潴留及其在组织中的分布，最显著的是肾脏，其次是大脑和肺。结果还表明，铜蓝蛋白与慢性升高的锰暴露相互作用，产生更高水平的脑氧化应激。这些结果提供了证据，表明金属氧化酶蛋白在改变因锰暴露升高而产生的神经毒性方面起重要作用。
